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Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)

Primary Purpose

Breast Cancer, Neoplasm, Breast, Breast Diseases

Status
Not yet recruiting
Phase
Phase 4
Locations
Poland
Study Type
Interventional
Intervention
Sacubitril-valsartan
Sponsored by
Silesian Centre for Heart Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Breast Cancer focused on measuring LCZ696, Sacubitril/Valsartan, Magnetic Resonance Imaging, Echocardiography, Cardio-oncology, Breast Cancer, Cardiotoxicity, Anthracyclines, Trastuzumab, Heart failure, Cardioprotection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Written informed consent
  • Female gender, aged 18 years and over
  • Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (ER, PR, HER2, Ki67)
  • Ability to take oral medication and willingness to adhere to the planned regimen
  • Tumor grade IA-IIIC or oligometastatic grade IV
  • Radical treatment plan including surgery
  • Plan of use of systemic treatment (preoperative, postoperative or combined) with anthracyclines and/or anti-HER2 drugs
  • ECOG 0-2 general status
  • LVEF ≥ 50% as assessed by echocardiography
  • Sinus rhythm

Exclusion Criteria:

  • Prior anthracycline-based chemotherapy and/or left-sided radiotherapy (prior to diagnosis of the cancer being the present cause of therapy)
  • Clinically relevant HF (NYHA II-IV)
  • MI within the last < 3 months
  • Symptomatic hypotension or SBP < 90 mmHg
  • Significant valvular disease, symptomatic coronary artery disease (CCS>2), significant AV block, symptomatic sinus node dysfunction
  • Expected survival <12 months
  • GFR<30 ml/min/1.73 m2 (screening visit)
  • K+>5.5mmol/L (screening visit)
  • Contraindications to ACE-I/ARB or LCZ696 if not listed among criteria
  • Active untreated liver disease
  • Pregnancy
  • Contraindications to cardiac MRI, including allergy to gadolinium-containing contrast agent or presence of implanted materials or devices prohibited for MRI
  • Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)

Sites / Locations

  • Regional Cancer Centre in Opole
  • Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch
  • Silesian Center for Heart Diseases
  • Holy Cross Cancer Centre, Cardio-Oncology Division

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Experimental: Sacubitril/Valsartan

Placebo

Arm Description

After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the experimental arm, the patients after randomization will receive the dose 200 mg b.i.d of sacubitril/valsartan for the course of the study. If the patients does not tolerate the target dose of 200 mg b.i.d., the reduction of the drug dose to 100 mg b.i.d. will be possible at the discretion of the physician-in-charge.

After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the placebo arm, the paitents will receive the matching placebo with an identical strategy of dose reduction as in the intervention group, at the discretion of the physician-in-charge.

Outcomes

Primary Outcome Measures

Decrease in left ventricular ejection fraction ≥ 5%
Reduction of LVEF assessed on magnetic resonance imaging (MRI)

Secondary Outcome Measures

Death from any cause or hospitalization for heart failure
Composite clinical endpoint
Death from any cause
Death from cardiovascular causes
Hospitalization for other cardiovascular causes
Decrease in left ventricular ejection fraction ≥ 5%
Reduction of LVEF assessed on echocardiography
Occurrence of diastolic dysfunction (UKG) within 24 months of randomization
Diastolic dysfunction assessed on echocardiography
- Development of pathological pericardial fluid volume or increase in pericardial fluid volume from baseline
Assessed with any available clinical modality
Occurrence of cardiac tamponade
Assessed with any clinical modality
Occurrence of pericarditis
Assessed with any clinical modality
Occurrence of myocarditis
Assessed with any clinical modality
Development of ventricular arrhythmias
Assessed with any clinical modality
Development of supraventricular arrhythmias
Assessed with any clinical modality
Presence of conduction disturbances
Assessed with any clinical modality
Changes in corrected QT interval
Changes in BNP, NT pro-BNP, troponin T or troponin I levels
Assessed with serial laboratory measurements

Full Information

First Posted
July 4, 2022
Last Updated
July 15, 2022
Sponsor
Silesian Centre for Heart Diseases
Collaborators
Medical Research Agency, Poland
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1. Study Identification

Unique Protocol Identification Number
NCT05465031
Brief Title
Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)
Official Title
Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
February 2023 (Anticipated)
Primary Completion Date
December 2027 (Anticipated)
Study Completion Date
February 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Silesian Centre for Heart Diseases
Collaborators
Medical Research Agency, Poland

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Breast cancer is the most commonly cancer in women in the overall global population. According to the World Cancer Research Fund International, there were more than 2.25 million new cases of breast cancer in women in 2020. Although the modern treatment strategies, based on the complex care, which consists of surgery, radiotherapy, hormone therapy, and targeted chemotherapy directed at specific cancer molecules have substantially reduced the risk of death due to breast cancer, their wide adoption results in the wider prevalence of cardiotoxicity, defined as either symptomatic heart failure, or asymptomatic contractile dysfunction. The occurrence of cardiotoxicity induced by anti-cancer therapies is estimated at 5-15%, and its development is the primary cause of therapy termination, which significantly reduces the probability of the efficacy of treatment. Several attempts have been made to determine the efficacious preventive strategy, which could diminish the risk of cancer-therapy induced cardiotoxicity. The results of the prior studies indicated a trend towards lower risk of troponin elevation, or left ventricular contractile dysfunction with the introduction of drugs interfering with the renin-angiotensin-aldosterone (RAA) axis, which constitute the primary treatment modality in heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan, the novel therapeutic agent, has been demonstrated to significantly improve prognosis in patients with HFrEF. Prior retrospective, small, single-center studies have shown that treatment with sacubitril/valsartan may reduce the risk of cancer-therapy induced cardiotoxicity, or reverse contractile dysfunction caused by anti-cancer therapy. However, no large randomized data confirmed these findings. Therefore, the Sacubitril/Valsartan in PriMAry preventIoN of the cardiotoxicity of systematic breaST canceR trEAtMent) study, has been designed to verify, whether the preventive use of sacubitril/valsartan administered in the doses recommended in patients with HFrEF in breast cancer patients undergoing adjuvant chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will reduce the incidence of cardiotoxicity defined as impaired left ventricular systolic function on cardiac magnetic resonance imaging (MRI). In the trial, a total of 480 patients with histologically confirmed breast cancer, who are eligible for chemotherapy with anthracyclines or anthracyclines and HER-2 monoclonal antibodies, will undergo 1:1 randomization to either preventive treatment with sacubitril/valsartan or placebo. The patients will be followed for 24 months, and will have repetitive efficacy and safety examinations, including echocardiography, MRI, electrocardiography including 24-h Holter monitoring, blood tests, functional capacity tests and quality of life assessment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Neoplasm, Breast, Breast Diseases, Antihypertensive Agents, Sacubitril/Valsartan, Angiotensin II Type 1 Receptor Blockers, Angiotensin Receptor Antagonists, Molecular Mechanisms of Pharmacological Action, Heart Failure, Cardiac Toxicity, Cancer, Therapy-Related, Cancer Therapy-Related Cardiac Dysfunction, Cardiotoxicity
Keywords
LCZ696, Sacubitril/Valsartan, Magnetic Resonance Imaging, Echocardiography, Cardio-oncology, Breast Cancer, Cardiotoxicity, Anthracyclines, Trastuzumab, Heart failure, Cardioprotection

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Double-blinded
Allocation
Randomized
Enrollment
600 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Experimental: Sacubitril/Valsartan
Arm Type
Experimental
Arm Description
After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the experimental arm, the patients after randomization will receive the dose 200 mg b.i.d of sacubitril/valsartan for the course of the study. If the patients does not tolerate the target dose of 200 mg b.i.d., the reduction of the drug dose to 100 mg b.i.d. will be possible at the discretion of the physician-in-charge.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
After assessment of the tolerance of the drug during the single-blind period, during the which the starting dose of the drug of 100 mg b.i.d. should be increased after two weeks to the target dose 200 mg b.i.d, the patients will be randomized in 1:1 ratio to either intervention or placebo group. In the placebo arm, the paitents will receive the matching placebo with an identical strategy of dose reduction as in the intervention group, at the discretion of the physician-in-charge.
Intervention Type
Drug
Intervention Name(s)
Sacubitril-valsartan
Intervention Description
Sacubitril/valsartan (Entresto®) administered in the target dose of 200 mg b.i.d. (97/103 mg of sacubitril and valsartan respectively) for the period of 24 months. In case of target dose intolerance, the physician-in-charge will be able to reduce the dose to 100 mg b.i.d. (49/51mg of sacubitril and valsartan respectively). Physicians will be strongly encouraged to evaluate the possibility of drug dose uptitration to the target dose of 200 mg b.i.d.
Primary Outcome Measure Information:
Title
Decrease in left ventricular ejection fraction ≥ 5%
Description
Reduction of LVEF assessed on magnetic resonance imaging (MRI)
Time Frame
At 12 months from the randomization visit
Secondary Outcome Measure Information:
Title
Death from any cause or hospitalization for heart failure
Description
Composite clinical endpoint
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Death from any cause
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Death from cardiovascular causes
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Hospitalization for other cardiovascular causes
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Decrease in left ventricular ejection fraction ≥ 5%
Description
Reduction of LVEF assessed on echocardiography
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Occurrence of diastolic dysfunction (UKG) within 24 months of randomization
Description
Diastolic dysfunction assessed on echocardiography
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
- Development of pathological pericardial fluid volume or increase in pericardial fluid volume from baseline
Description
Assessed with any available clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Occurrence of cardiac tamponade
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Occurrence of pericarditis
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Occurrence of myocarditis
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Development of ventricular arrhythmias
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Development of supraventricular arrhythmias
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Presence of conduction disturbances
Description
Assessed with any clinical modality
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Changes in corrected QT interval
Time Frame
From Randomization till the end of blinded therapy - at 24 months
Title
Changes in BNP, NT pro-BNP, troponin T or troponin I levels
Description
Assessed with serial laboratory measurements
Time Frame
From Randomization till the end of blinded therapy - at 24 months

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
As breast cancer is primarily the female malignancy, the studied population will be limited to female patients
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent Female gender, aged 18 years and over Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (ER, PR, HER2, Ki67) Ability to take oral medication and willingness to adhere to the planned regimen Tumor grade IA-IIIC or oligometastatic grade IV Radical treatment plan including surgery Plan of use of systemic treatment (preoperative, postoperative or combined) with anthracyclines and/or anti-HER2 drugs ECOG 0-2 general status LVEF ≥ 50% as assessed by echocardiography Sinus rhythm Exclusion Criteria: Prior anthracycline-based chemotherapy and/or left-sided radiotherapy (prior to diagnosis of the cancer being the present cause of therapy) Clinically relevant HF (NYHA II-IV) MI within the last < 3 months Symptomatic hypotension or SBP < 90 mmHg Significant valvular disease, symptomatic coronary artery disease (CCS>2), significant AV block, symptomatic sinus node dysfunction Expected survival <12 months GFR<30 ml/min/1.73 m2 (screening visit) K+>5.5mmol/L (screening visit) Contraindications to ACE-I/ARB or LCZ696 if not listed among criteria Active untreated liver disease Pregnancy Contraindications to cardiac MRI, including allergy to gadolinium-containing contrast agent or presence of implanted materials or devices prohibited for MRI Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mateusz Tajstra, MD, PhD, Associate Professor
Phone
+48323733860
Email
mateusztajstra@wp.pl
First Name & Middle Initial & Last Name or Official Title & Degree
Lucyna Broja
Phone
+48323733853
Email
l.broja@sccs.pl
Facility Information:
Facility Name
Regional Cancer Centre in Opole
City
Opole
State/Province
Opolskie
ZIP/Postal Code
45-061
Country
Poland
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara Radecka, MD, PhD
Phone
+48774416001
Email
brad@onkologia.opole.pl
Facility Name
Maria Sklodowska-Curie Institute - Oncology Centre (MSCI), Gliwice Branch
City
Gliwice
State/Province
Silesia
ZIP/Postal Code
44102
Country
Poland
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michal Jarząb, MD, PhD, Associate Professor
Phone
+48322788886
Email
onkologia@io.gliwice.pl
Facility Name
Silesian Center for Heart Diseases
City
Zabrze
State/Province
Silesia
ZIP/Postal Code
41800
Country
Poland
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mateusz Tajstra, MD, PhD, Associate Professor
Phone
+48323733860
Email
mateusztajstra@wp.pl
First Name & Middle Initial & Last Name & Degree
Lucyna Broja
Phone
+48323733853
Email
l.broja@sccs.pl
Facility Name
Holy Cross Cancer Centre, Cardio-Oncology Division
City
Kielce
State/Province
Świętokrzyskie
ZIP/Postal Code
25-734
Country
Poland
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Barbara Sosnowska-Pasiarska, MD, PhD
Phone
+48 41 34 56 882
Email
repikus@poczta.onet.pl

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)

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